FDA Issues Two Key ASO-Related Guidances for N-of-1 Trials

FDA Office

The FDA has issued two draft guidances for clinical trials and manufacturing for N-of-1, or single person, trials of antisense oligonucleotide (ASO) therapies for ultra-rare diseases.

“Progress in individualized medicines provides hope to patients with severely debilitating or life-threatening genetic diseases,” said acting FDA Commissioner Janet Woodcock, M.D. in a press release about the guidances.

The first guidance includes recommendations for managing the administration of ASOs in a clinical trial and conducting clinical assessments of the safety and response during administration of the investigational drug.

It describes important clinical considerations for investigational new drug application (IND) submissions to support initial and continued administration, dosing and clinical monitoring of individuals who participate. The draft guidance is specifically tailored to the unique circumstances involving relatively few (typically one or two) individuals.

The guidance states that it’s focus is to inform, “…investigational new drug application (IND) submissions to support initial and continued administration, dosing, and clinical monitoring of an individual with a SDLT [severely debilitating or life-threatening] genetic disease attributable to a unique genetic variant(s) that may be amenable to an ASO drug product.”

The second draft guidance provides recommendations regarding the chemistry, manufacturing and controls information that should be provided in an IND application for certain types of ASO drugs. This includes information regarding drug quality (e.g., chemical structure, manufacturing process and critical quality attributes) and manufacturing guidelines.

The agency notes that the field of N-of-1 trials is rapidly evolving, and antisense oligonucleotide drugs are the most advanced in this space. However, many single patient trials are carried out by academic investigators who may not have much experience interacting with the FDA.

In January of this year, the FDA provided an initial draft guidance to investigators carrying out such work.  That guidance emphasizes the important of early interaction with the agency as well as having an established communication plan.  It also outlines formalities such as the content and format of the pre-IND meeting package, the elements of the application, and ethical and human subject protection considerations.

Said Woodcook in this week’s press release, “Today, we are issuing additional draft guidance in this area. Once finalized, this guidance will detail important clinical and production considerations to support applications for these types of clinical trials and drug development programs.”

She added that, “The FDA is hopeful these draft guidances, once finalized, will help promising drugs reach patients in a timely manner. We are optimistic that the development of these individualized drug products may continue to change the landscape for treating rare diseases, and the FDA is committed to providing resources and guidance to those advancing these technologies to treat patients in need.”

In a 2019 NEJM editorial, Woodcock and her associate Peter Marks commented on an ASO therapy designed for a single patient with CLN7 neuronal ceroid lipofuscinosis (a form of Baten’s disease). They asked, “On a larger scale, we need to consider how such truncated programs fit into the spectrum of drug development in general: what are the differences between treating one, ten, or thousands of patients?”

They pointed out that, thanks to advances in technology, even academic clinician–investigators can uncover specific mutations and pinpoint the putative mechanisms underlying rare disease phenotypes. In addition, “Various ASOs or other compounds can be produced by third parties, and investigators can evaluate them using in vitro assays or animal models. Similarly, genetic constructs can be developed for cell-based or directly administered gene therapy.”


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